Drug-induced myoclonus: Antidepressants, lithium, and anticonvulsants can be responsible for myoclonic encephalopathy.
Benign essential myoclonus: Benign essential myoclonus has its onset in childhood and adolescence and is inherited autosomal dominant. Dystonia can be part of the clinical picture. The EEG is normal. The jerks are alcohol sensitive and the disease is non-progressive.
Juvenile myoclonic epilepsy (JME): This form of epilepsy, accounting for almost 10% of all individuals with epilepsy, consists of a triad of absence (>30% of patients), jerks on awakening and GTCS. Absence, when present, starts in the fist decade, myoclonic jerks usually follow at the age of 14-15 years and a few months later GTCS occur. The history of myoclonus is the clue to the diagnosis and can start anytime between 10 and 25 years and are symmetric myoclonic jerks, usually in the upper limbs and in the morning on awakening. There may however be a second peak in the evening. Up to 60% of patients have a positive family history. Sleep deprivation, fatigue and alcohol appear to be potent provocative factors. The EEG reveals 4 to 6 Hz bilateral symmetric polyspike-wave complexes or 2-3 Hz spike wave complexes. Photosensitivity is common (>70%). Up to 12% of first-degree relatives who do not have seizures have abnormal EEG. EEG on sleep and awakening should be done if routine EEG is normal. The inheritance pattern is variable and the gene (EJM1) has been identified on chromosome 6p21. JME responds to treatment with sodium valproate (up to 90% of patients with JME become seizure-free with valproate monotherapy). Newer broad spectrum drugs such as topiramate, and possibly levetiracetam, may also be of benefit. Myoclonic jerks respond well to clonazepam. Phenytoin and carbamazepine have shown to aggravate the myoclonic and absence seizures of JME and therefore should be avoided. The absence of accompanying neurological (usually cognitive) decline distinguishes JME from progressive myoclonic epilepsies. Furthermore, JME should be differentiated from hypnagogic myoclonus.
Familial adult myoclonic epilepsy (FAME): FAME is characterized by autosomal dominant inheritance, adult onset myoclonic of the extremities, and triggered by fatigue, insomnia or photic stimulation, myoclonic jerks upon awakening, tremulous finger movements and infrequent generalized seizures. Electrophysiological findings reveal giant SSEP and EEG shows general spikes or polyspikes and slow wave complexes. The gene is mapped at chromosome 8q24. Absence of neurological deterioration distinguishes FAME from Lafora body disease (EPM2A).
Postanoxic myoclonus: Cerebral anoxic myoclonus occurs following CRA due to asthma, patients may present with myoclonus in addition to cognitive impairment, epilepsy, spasticity and ataxia.
Whipple disease: This rare disorder is predominantly found in middle-aged men. The triad of cognitive changes (half of them with psychiatric features) (71%), myoclonus (31%) and eye movement abnormalities (vertical supranuclear gaze palsy, INO, oculomasticatory or facial-skeletal myorhythmia) (20%) is diagnostic for Whipple disease but is only found in 10% of patients. In addition, focal cerebral and cerebellar syndrome, aseptic meningitis (mild pleocytosis with occasssionally PAS positive material), headache and epilepsy may be found. This may occur independently of the gastrointestinal malabsorption (steatorrhea, abdominal pain and distention, weight loss, wasting) or systemic features (hyperpigmentation, fever of unknown origin, lymphadenopathy, longstanding remitting and relapsing arthropathy) of the disorder (up to 15%). The diagnosis is established by small bowel biopsy or more reliable by PCR on biopsy or CSF. The causative agent is Tropheryma whippelii, which can be found in bowel and brain tissue. Neuroimaging is non-specific and mimics TB, sarcoidosis, AIDS, MS and encephalitis. Most commonly the disease is misdiagnosed as AD and later on CJD. Other differential diagnosis include neurosarcoidosis and cerebral vasculitis.
Celiac disease (or gluten sensitive enteropathy): The age of onset may vary between 40 - 80 years and the mean duration of ataxia between 3 to 25 years. Half of the patients do not present with gastrointestinal symptoms (gluten-sensitive enteropathy or celiac disease). Neurologic manifestations and dermatitis herpetiformis can occur without histologic evidence of bowel involvement. Majority of patients presenting with neurologic symptoms have peripheral neuropathy (often painful sensory neuropathy) or cerebellar ataxia ("gluten ataxia"). Other neurological features may include episodic unilateral headache with visual disturbances (hemianopia), deafness, encephalopathy (confusion, agitation, dementia), myelopathy, cerebral calcification and seizures. Some patients develop Ramsay-Hunt syndrome. The diagnosis is based on small bowel biopsy or the presence of serum IgA anti-gliadin and IgA endomysial antibodies. Up to 90% of patients with celiac disease are HLA DQ2, the remaining have DQ8 or DQ1. Brain MRI abnormalities vary from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Only 33% of patients presenting with neurologic dysfunction associated with gluten sensitivity also have celiac disease. Gluten ataxia accounts for 40% of cases of idiopathic sporadic and familial cerebellar degeneration. The neurological manifestations may not respond to a gluten free diet.
Mitochondrial disease: Mitochondrial disease can be a cause of progressive myoclonic ataxia.
Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome (HHHS): The hallmark of this autosomal recessive disease consists of pyramidal tract dysfunction with aversion for protein-rich food and characteristic signs of hyperammonemia. Clinical features include spastic paraparesis, myoclonic seizures, mental retardation, and ataxia. Furthermore, there are recurrent acute episodes of hyperammonemia with loss of consciousness, lethargy and coma. Liver disease and coaguloapthy may occur. Age at onset may be variable (neonatal to early adulthood). The diagnosis is based on determination of plasma and urine amino acids, blood ammonia, and urinary orotate. Brain MRI may be normal or show basal ganglia calcifications or cortical atrophy. Liver and skin fibroblasts biopsy show giant megoconial mitochondria. The mutation has been identified in the gene that encodes for the mitochondrial ornithine transporter (SLC25A15 gene).
Myoclonic epilepsy with ragged red fibers (MERRF): The age of onset of this disease ranges from 5 – 75 years. The core clinical features of MERRF are myoclonus (often action, noise or photic stimulation-induced), progressive ataxia and seizures (drop attacks, focal seizures and photosensitive tonic-clonic seizures). Generalized myoclonic seizures are an early and consistent symptom only in a minority of patients with MERRF. Myopathy is usually proximal and mild (or may even be absent). Ragged-red fibers (not found in all patients) COX negative are the diagnostic histopathologic features in the muscle biopsy specimen. Additional features are progressive external ophthalmoplegia, progressive sensorineural hearing loss, peripheral neuropathy, foot deformity, basal ganglia calcification, short stature, deafness, OA and cervical lipomas. Insidious dementia may develop later in the course of the disease. Pigmentary retinopathy is found only in mtDNA mutations other than A8344G mutation. Plasma and CSF lactate levels can be elevated, but this is not a universal finding. The disorder is caused most commonly by a point mutation (A8344G) in the tRNA gene of mitochondrial DNA. The disorder can occur any time in adult life and the course is slowly or rapidly progressive. Maternal inheritance is an important feature that distinguishes MERRF from four other neurological syndromes dominated by progressive myoclonic epilepsy: Unverricht-Lundborg disease (EPM1), Lafora body disease (EPM2A), Gaucher disease (neuronopathic form) sialidosis type I and II, NPC, juvenile GM2/GM1 gangliosidosis and Kufs disease.
Lafora-body disease (EPM2): This is an autosomal recessive disorder with late childhood or teenage onset and is characterized by progressive myoclonus and generalized tonic-clonic epilepsy (photoconvulsive seizures), drop attacks, ataxia and rapidly progressive dementia. Brain MRI shows often cerebellar atrophy. The diagnosis is made by biopsy (skin, muscle, liver, brain) showing periodic acid-Schiff positive glycogen-like intracellular inclusion bodies (Lafora bodies). The mutation in the EPM2A gene which codes for laforin and which probably prevents accumulation of polyglucosans bodies in healthy neurons has been mapped to chromosome 6q24. The second type is a mutation in EPM2B gene which codes for E3 ubiquitin ligase (malin). Prognosis is poor (death within 10 years). Other forms of autosomal recessive PME are Unverricht-Lundborg syndrome (EPM1), Mediterranean and Baltic myoclonus epilepsy syndrome. The latter is accelerated by phenytoin.
Unverricht-Lundborg disease (EPM1): This autosomal recessive disorder with severe stimulus-sensitive myoclonus and generalized tonic-clonic seizures typically begins between the age of 6 - 15. Seizures become less frequent in young adult life. Progressive cerebellar ataxia develops in addition to mild dementia. The disease is prevalent around the Baltic area. Unlike in other PMEs, no inclusion bodies or storage material are found. With exclusion of other forms of PME, generalized epileptiform discharges on EEG activated with intermittent photic stimulation are pathognomonic. The gene (cystatin B) responsible for the disorder is mapped to chromosome 21q22.3. Brain MRI reveals loss of bulk of basis pontis, medulla, cerebellar hemispheres, and widening of the interhemispheric cerebral sulci due to atrophy. Life expectancy is over 60 years of age, but disability is often severe. Piracetam has been useful in the treatment of myoclonus. Phenytoin aggravates symptoms.
Sialidosis type I or cherry-red spot – myoclonus syndrome: Type I sialidosis is the mild form and starts in adolescence or adulthood (2nd or 3rd decade of life) presenting with bilateral macular cherry-red spots and bilateral perinuclear cataracts (progressive loss of visual acuity), progressive cerebellar ataxia, progressive stimulus-sensitive myoclonus (affecting the face and limbs and triggered by voluntary movements) and seizures (tonic-clonic) and mild peripheral polyneuropathy (burning feet). No dismorphic features are present. The diagnosis is made by elevated urinary sialyloligosaccharides, vacuolated white cells and foam cells with white cell a-N-neuraminidase deficiency. The mutated sialidase gene is located on chromosome 6p21.3. Brain MRI may reveal severe atrophy of the cerebellum, pontine region, cerebral hemispheres and corpus callosum. Sialidosis is inherited as an autosomal recessive genetic trait.
Opsoclonus-myoclonus syndrome: In adults this syndrome is idiopathic in 50% of cases. Post-infectious, paraneoplastic or toxic cases account for the remainder.
Three clinically distinct neurologic syndromes have been identified of this
autosomal recessive lysosomal disorder characterized by
deficiency: type I (chronic non-neuronopathic), type II (acute neuronopathic),
and type III (subacute or chronic neuronopathic). Adult forms have been reported
in type I and III. Although non-neuronopathic, Gaucher type I may present with
atypical PD in the 4th - 6th decade. The clinical course
is usually severe with aggressive progression and is refractory to levodopa
therapy. Gaucher type III (chronic neuronopathic form) is a chronic, slowly
progressive neurologic disorder which may develop in early adult life.
Stimulus-sensitive myoclonus, generalized seizures, horizontal supranuclear gaze
palsies, and cerebellar ataxia are the main clinical features. Certain ethnic
groups are at risk for this disorders; Gaucher type I is commonly found in
Ashkenazi Jews (incidence of 1 in 2,500 births), while type III is more common in
Northern Sweden (Norbotten). The diagnosis is based on the measurement of
activity in white blood cells. The clinical course is not predictable by
measurement of residual
activity. The disorder is caused by a mutation in the gene on chromosome 1q21.
Lewy body disease (LBD): The disease is more common in men than women with a ratio of 2:1. The mean age at onset of symptoms is around 70 years. The diagnostic criteria for LBD are at least one of the following: 1) early fluctuating mental state with episodic delirium, 2) prominent psychiatric symptoms such as depression, florid visual and/or auditory hallucinations (recurrent and detailed; involves animals and people) and paranoid ideation and 3) strikingly asymmetric extrapyramidal syndrome (parkinsonism often only gait abnormalities with postural instability, lack of tremor) spontaneously or associated with neuroleptic therapy. Secondary features are: repeated falls, syncope and transient loss of consciousness, high-sensitivity to neuroleptic drugs (e.g. persistence of parkinsonism after discontinuation of neuroleptic therapy), delusions and non-visual hallucinations. Dementia is the major feature with poor memory often being the initial sign, and often precedes, follows, or coexists with parkinsonism. Sometimes dementia is the only clinical feature. Rare clinical features are limb myoclonus and supranuclear gaze palsy. LBD progresses faster than AD. There is generally little response to levodopa therapy. LBD represents 15 - 30% of all cases of dementia at autopsy. These clinical criteria, when compared with the reference standard of autopsy, have been found to be highly specific (79-100%) but to lack sensitivity (22-75%), implying that these criteria are useful for confirming the diagnosis but cannot be relied on for screening. The differential diagnosis is difficult particularly in those patients with “typical levodopa responsive IPD for years” who then develop confusion and hallucinations, or atypical cases with myoclonus (differential diagnosis with CJD) or supranuclear gaze palsy (differential diagnosis with PSP), and should be suspected in patients with dopaminergic therapy exacerbated confusion and neuroleptic-induced parkinsonism. Diagnosis is often made at autopsy! Biopsy differences from AD in that: ubiquitin-positive neurites in hippocampus are found and with no neurofibrillary tangles in cortex. The average time from onset to death is 6.4 years, with the most frequent cause of death being aspiration pneumonia.
Corticobasal ganglionic degeneration (CBGD): This sporadic degenerative disorder occurs after the age of 60 years and is characterized by a striking asymmetric parkinsonism and localized cortical deficits. The most common signs and symptoms in descending order are: asymmetric limb rigidity (100%), upper limb apraxia (91%), gait difficulties (89%), stimulation-sensitive focal myoclonus (88%), eye movement abnormalities (particularly in later stages supranuclear horizontal or vertical gaze saccadic palsy) (78%), limb dystonia (77%), pyramidal signs (73%), dysarthria (62%), cortical sensory abnormalities (55%), and the "alien limb" phenomenon (55%). Early falling and postural instability are also common. Typically one extremity may be in a dystonic posture and exhibit dyspraxia. The response to levodopa therapy is poor and progression to FTLD is common. Therefore some clinical overlap between CBGD and FTDP and FTLD may occur. The diagnosis of CBGD is ultimately clinical. Neuroimaging of the brain may reveal pontine atrophy and asymmetrical frontoparietal cerebral atrophy corresponding to the symptomatic side in about 50% of cases, whereas atrophy is symmetric in the other 50%. The prognosis is poor with an average survival rate of 5 - 10 years. Differential diagnosis should include levodopa responsive parkinsonism, ataxia, and progressive myoclonic epilepsy, AD, PSP, MSA, hemiparkinsonism, and FTDP and FTLD.
Creutzfeldt-Jacob disease (CJD): The annual incidence of this prion disorder is 1/million in the general population, 90% being sporadic in nature. Libyan Jews, North African immigrants to France and Slovakians have a higher incidence of developing the disease. Infected corneal transplants, deep brain electrodes, dural grafts and growth hormone preparations have been causes of transmission. The peak age of onset ranges from 55 to 75 years of age. The clinical diagnostic criteria for CJD are: rapidly progressive dementia (confusion, hallucinations, delusions, agitation, changes in visual perception)(<2 years) with periodic sharp wave complexes in the EEG in addition to two of the following: stimulus-sensitive myoclonus (startle reactions), ataxia or visual symptoms, parkinsonism or pyramidal signs, or akinetic mutism. Associated findings are weight loss, anorexia and insomnia. There is paucity of lab abnormalities: CSF may show elevated protein (around 100 mg/dl) and up to 20% of patients may have oligoclonal bands on CSF electrophoresis. CSF 14-3-3 immunoblot (sensitivity 94%, specificity 84-97%) and tau-protein ELISA (Innogenetics, Ghent, Belgium) (sensitivity 94%, specificity 90%) are positive predictors in over 90% in CJD. EEG findings may be normal or reveal only slowing of background activity, especially early in the course of disease. Initially non-specific changes are observed but later on bilateral synchronous high voltage periodic triphasic sharp wave complexes 0.5 - 2 Hz (sensitivity 67%, specificity 74-86%) are seen. However, the absence of these sharp wave complexes does not rule out the diagnosis of CJD. Brain MRI shows symmetric hyperintense abnormalities in putamen, thalamus and cortex (gyral swelling) on T2 images, which may be supportive for the diagnosis. On T1 images these lesions remain isointense and do not enhance after contrast. FLAIR sequences are preferred, as they may show hyperintense areas of gray matter, particularly in the cerebral cortex, not otherwise appreciated on conventional T2-weighted images. Diffusion-weighted MRI scans may suggest that abnormal cortical signal results from intracellular edema or cytotoxicity. Olfactory (and brain) biopsy may provide diagnostic information in living patients (the conversion of a normal cellular protein (PrPC) to an abnormal isoform, PrPSC). Mean interval between onset and death is 8 months. Precautions should be taken when handling all body fluids of an infected patient, especially spinal fluid. Gloves should be worn during procedures (e.g. lumbar puncture) and accidental skin contamination should be rinsed with a 1:10 dilution of sodium hypochlorite (household bleach). Specimens from known or suspected infected patients should be marked as such, so that laboratories may handle and dispose of them appropriately.
Several clinical variants have been described: Heidenhaim variant: typically associated with florid visual hallucinations and cortical blindness. Brownell-Oppenheimer variant: predominantly cerebellar ataxia with little cognitive involvement. Stern-Garcia variant: predominantly basal ganglia and thalamic form.
Subacute necrotizing encephalopathy (SNE) or Leigh disease: Several synonyms exist such as Leigh necrotizing encephalopathy, subacute necrotizing encephalopathy, Leigh syndrome and necrotizing, encephalomyelopathy of Leigh. Adult-onset forms of SNE are sporadic, or inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial trait. To complicate matters even more several different types of genetically determined enzyme defects can cause SNE. As with other mitochondrial disorders, the onset of neurologic symptoms present from the 1st to 6th decade with acute or subacute onset, often precipitated by surgical intervention or febrile illness. The disease can present with a variety of symptoms such as brainstem dysfunction (central respiratory failure, intermittent oculomotor palsy, cranial nerve dysfunction including deafness, optic atrophy or Wernicke-like syndrome), ataxia, or extrapyramidal (dystonia) symptoms, global cognitive (dementia or mental retardation 30% of patients), spastic paresis, myoclonic jerks and seizures, peripheral demyelinating polyneuropathy, motor decline and unconsciousness with lactic acidosis. In addition, insulin-resistant diabetes mellitus, muscular weakness, intractable nausea and vomiting, and anemia can occur. Pyruvate dehydrogenase deficiency which is autosomal recessive presents with episodic ataxia, seizures, and hypoglycemic episodes. The disease can be intermittent progressive or remitting/relapsing. CSF protein may be increased. Brain MRI shows abnormal high intensities in basal ganglia, particularly putamen, on T2 weighted images, bilateral medial regions of the thalamus, brainstem and periaqueductal gray matters. Proton MRS may show elevated lactate level in involved regions of the brain. Ragged red fibers can be found on muscle biopsy with increased succinic dehydrogenase activity and cytochrome oxidase negative fibres in almost 90% of cases. Pre- and postprandial serum and CSF lactate and pyruvate are useful in the diagnosis. Serum lactate is increased in 50% of patients but is less sensitive than CSF lactate. Treatment for SNE is empirical but the administration of thiamine, vitamin B1, Coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.
Panthotenate kinase-associated neurodegeneration or Hallervorden-Spatz disease (HSD): The adult onset form of this autosomal recessive disorder presents in early adulthood with atypical parkinsonism (initially affecting the legs or bulbar musculature), ataxia, myoclonus, dystonia (tongue or blepharospams), chorea or dementia. Most patients also develop pyramidal syndrome and seizures (20%). T2 weighted brain MRI shows an ”eye of the tiger” sign corresponding to pallidal hypointensity with a high signal center. Very low signal intensity is also seen in the red nucleus, and substantia nigra, consistent with increased iron deposition in these structures. Bone marrow contains sea blue histiocytes. The gene locus (PANK2) has been identified on chromosome 20. Treatment of patients with HSD is largely symptomatic. Many patients, especially in the early stages of the disease, may respond modestly to levodopa treatment. Variants have been reported such as HARP syndrome (hypoprebetalipoproteinemia [very low VLDL], acanthocytosis, retinitis pigmentosa, and pallidal degeneration). The dystonia affects cranial musculature and MRI findings are those of HSD. HSD needs to be differentiated from WD, juvenile HD, SNE, PD, DRD, Fahr disease, Lafora body disease (EPM2), MS, DRPLA, Kufs disease, gangliosidoses and APBD.
Kufs disease type A (adult neuronal ceroid lipofuscinosis): In adolescence to middle age adulthood, two clinical Kufs phenotypes emerge; type A, featuring progressive myoclonic epilepsy with marked photosensitive and generalized tonic-clonic seizures developing at around the age of 30 years with subsequent ataxia, and dysarthria, dementia, and later pyramidal and extrapyramidal signs. There are no visual problems and seizures are often refractory; and type B, dominated by neuropsychiatric symptoms, including behavioral disturbances and dementia, and may be associated with cerebellar or extrapyramidal signs (cranial dystonia including facial dyskinesias or parkinsonism). The dementia syndrome is characterized by gradual onset, progressive course, and deficits in episodic memory, executive function, and visuospatial abilities; these features and the pattern of cognitive dysfunction thus overlap those of more common neurodegenerative dementing illnesses, including AD. Dementia may be the presenting symptom of Kufs disease and may not be manifested until the seventh decade of life. Unlike other forms of neuronal ceroid-lipofuscinosis, it does not cause blindness. Electrophysiologic and neuroradiologic studies are nonspecific. Giant VEP and large SSEPs can be elicited. Abnormal photic drive (high-amplitude spike at low rates of stimulation) is observed during EEG. Brain MRI may show predominantly cerebellar atrophy and signal changes on T2 in the putamina. The diagnosis is based on the presence of granular osmiophilic deposits found by EM in rectal, muscle, skin or liver biopsy and are deficient in lysosomal palmitoyl protein thioesterase. Urinary sediment dolichol levels are elevated in both types. The disease is autosomal recessive (rarely dominant) and caused by mutation in CLN3 gene of which the locus is unknown. Kufs disease should be considered when seizures and motor disturbances complicate the early course of atypical dementia in middle adult life. Visual loss and optic atrophy are unusual and in combination with the later age at onset clinically distinguished Kufs disease from other NCLs. Mean length of illness is about 7 years.
Although described chiefly in Japan, European families are also affected by this
autosomal dominant condition. It is caused by a CAG repeat expansion mutation of
atrophin 1 gene mapped to chromosome
12p13 (Boston University Center, Human Genetics Laboratories).
The age of onset of symptoms ranges from adolescence to the 6th
decade of life and the presentation is quite heterogeneous. Three phenotypes
have been described the ataxo-choreoathetoid type, a pseudo-Huntington type, and
a myoclonic epileptic type. Hence clinical features include progressive cerebellar ataxia,
or dementia with chorea, or prominent chorea and dystonia or
progressive myoclonic epilepsy. Variants (Haw-River syndrome) of the disease
exist (subcortical demyelination; neuroaxonal dystrophy; no seizures).
Brain MRI scan shows cerebellar and brainstem atrophy and multiple WMHIs on T2 sequences. DNA analysis is essential for the diagnosis. Homozygotes
for DRPLA genes may have recessive predominantly spinal syndrome which has its
onset in the 3rd or 4th decade and consists of spastic
paraplegia, loss of vibratory in the lower limbs and truncal ataxia.
view of its resemblance DRPLA is often confused with HD.
Subacute sclerosing panencephalitis (SSPE): SSPE is a neurodegenerative disease due to persistent rubeola (measles) infection that affects children and young adults. Onset of the disease is insidious and often only recognized after significant neurologic deficits occur. The diagnosis of SSPE can be made if three of the following five criteria are fulfilled: 1) typical clinical presentation with progressive cognitive decline and stereotypical myoclonus (sustained myoclonus), 2) characteristic EEG changes, 3) elevated cerebrospinal fluid globulin levels without pleocytosis, 4) elevated CSF measles antibody titers, and 5) typical histopathologic findings in a brain biopsy or autopsy. Affected individuals progress through four loosely defined clinical stages at differing rates. Stage I is characterized by subtle behavioral changes, cognitive decline, emotional lability, lethargy, and nonspecific neurologic symptoms. This stage may last for weeks to months. Stage II includes continued intellectual decline, myoclonus, focal seizures with secondary generalization, choreoathetosis, apraxia, and visual changes with optic atrophy, dysarthria, and tremors. A wide variety of visual disorders have been associated with SSPE, including papilledema, retinitis, chorioretinitis, optic nerve pallor, homonymous visual field deficits, and cortical blindness. This stage may last three months or less. Neurologic decline persists in stage III (decreased level of consciousness, autonomic instability (with a variable heart rate and widely fluctuating temperatures and blood pressures), dystonia and rigidity, decorticate/decerebrate posturing), but the pace slows down, and symptoms may stabilize for one to two years. Features of stage IV include active startle reflex, flexor limb positioning, quadraparesis, akinetic mutism, wandering eye movements and coma. At this time, myoclonus, seizures, and rigidity are less frequent than in prior stages. CSF reveals markedly elevated intrathecal IgG synthesis rate and multiple oligoclonal bands in the gamma region on high-resolution electrophoresis, without a cellular reaction. Serum and CSF rubeola IgG titers are elevated with normal IgM titers. The EEG exhibits periodic complexes with generalized bilateral, usually synchronous and symmetrical sharp and slow wave complexes of high amplitude (greater than 500 uV), classically occurring every 5-10 seconds. Early in the course of the disease these periodic discharges may occur on a normal background but later the background becomes increasingly slower and disrupted. These periodic complexes are usually associated with clinically evident myoclonic or dystonic activity. MRI may be normal or may show early changes of increased signal on T2-weighted sequences, frequently involving the periventricular or subcortical white matter in the frontal, temporal, and occipital white matter; late changes include significant white matter loss, approximately 30% of patients show basal ganglia changes, while 25% have cortical changes. Fifty percent of patients who develop SSPE had measles (rubeola) before two years of age, and 80% before age four years. Five percent of patients survive three months or less and 20% survive four or more years, with a mean survival of only 18 months. Death occurs in stage IV, often the result of intercurrent illnesses such as pneumonia. MS (visual changes, oligoclonal bands) is often considered in the differential diagnosis of SSPE. Treatment is disappointing. The most promising results to date have used a combination of inosiplex, an antiviral agent, and intraventricular or intrathecal alpha-interferon as an immunomodulator, with stabilization or improvement in some patients. Early childhood measles vaccinations remain critical in limiting the incidence of SSPE.